An average of over 7,500 large copy and paste DNA insertions occurs in each human brain as somatic mutations, i.e., DNA mutations that occur post-fertilization. Because of the large size of the insertions, they are termed structural genomic mutations. The mechanism of such mutations is mainly retrotransposition of transposable elements in the human genome. This phenomenon may prove relevant to Alzheimer's disease (AD), where somatic mutation hypotheses have been repeatedly proposed. These mutations are thought to lead to AD by interacting with inherited susceptibility variants, in a multiple-hit manner. We propose here to detect somatic mutations, including both point mutations and structural genomic mutations, in temporal cortex in a small sample of 7 AD patients and 7 controls, with two methods of mutation detection, and independent validation of each method. The two complementary methods for somatic mutation detection are microarray- based Transposon Insertion site Profiling (TIP-chip) capture coupled with sequencing (RC-Seq) and paired- end whole-genome sequencing (WGS). We will demonstrate the somatic nature of each mutation by comparison of brain and liver sequences in each individual. Comparative evaluation will inform our choice of methods for future studies. If justified by results of this stdy, we will next propose a large-scale case-control study, to determine if there is a somatic mutational burden, and/or specific genes impacted by somatic mutations, in AD. The PIs in this proposal include Dr. Geoff Faulkner, a pioneer in somatic mutations whose lab produced the 2011 Nature paper reporting the discovery of high-frequency somatic mutations in adult human brain, and Drs. Chunyu Liu and Elliot Gershon, who have published extensively on structural genomics, epigenetics, and bioinformatics in neuropsychiatric disorders.